Claims:We claim,

1. A process for preparation of highly pure Ethyl-dec-9-ynoate (III), which process comprises;
a) oxidizing 9-Decyn-1-ol of formula (I) with NaClO2 / NaOCl in presence of TEMPO/ NaH2PO4 in a solvent system to obtain Dec-9-ynoic acid (II);
b) purifying the Dec-9-ynoic acid (II) by converting into its Potassium salt followed by neutralizing with a mineral acid; and
c) esterifying the Dec-9-ynoic acid (II) by treating with Ethanol/Sulphuric acid followed by neutralization to obtain Ethyl dec-9-ynoate(III).

2. The process according to claim 1, wherein, the equivalence of NaOCl and NaClO2 in the ratio of 0.3-1.7.

3. The process according to claim 1, wherein, the solvent system is monophasic system selected from the group consisting of Water; Water/Acetonitrile, Water/Acetone.

4. The process according to claim 1, wherein, the reaction of step a) is conducted at ambient temperature, preferably in the range of 25 to 40?C.

5. The process according to claim 1, wherein, the reaction pH of Dec-9-ynoic acid is in the range of 6.5-9.0.

6. The process according to claim 1, wherein, the isolation of Dec-9-ynoic acid is carried out at pH of 3.5-4.0.

7. The process according to claim 1, wherein, the Potassium salt of Dec-9-ynoic acid is purified from IPA.
8. The process according to claim any one of the preceding claims, wherein, the impurity of 1-Decanoic acid ethyl ester (VI) and Ethyl non-8-ynoate (VIII) are controlled to less than 0.5%.
, Description:Technical filed:
The present invention relates to a process for preparation of Ethyl-dec-9-ynoate (III). More particularly, the invention relates to highly pure Ethyl-dec-9-ynoate (III), wherein, the process impurities such as 1-Decanoic acid ethyl ester (VI) and Ethyl non-8-ynoate (VIII) are controlled to less than 0.5%.

Background and prior art:
Ethyl-dec-9-ynoate also, known as 9-Decynoic acid ethyl ester, is a chemical intermediate useful in the synthesis of Linoleic acid, and also an early stage intermediate/building block for certain active pharmaceutical ingredients that are currently under development.

The synthesis of 9-Decynoic acid ethyl ester is disclosed in RSC Advances, 2013, 3, 19040-19050. The synthesis of 9-Decynoic acid ethyl ester comprises oxidation of 9-Decynol with Pyridinium dichromate for 3 days under stirring to obtain 9-Decynoic acid as a colourless oil, which is reacted with Ethanol in presence of p-Toluenesulfonic acid for 6 hrs to obtain 9-Decynoic ethyl ester.
The present inventors have observed that when the oxidation of 9-Dec-yn-1-ol (I) is carried out using Jones reagent, a new impurity, Non-8-ynoic acid (VII), is observed up to 8%. Being closely related by having the same functionality, the impurity is difficult to separate and is carried till the final product and could not be reduced or removed by further purification.

Therefore, it was felt that there remains a need in the art to synthesize highly pure Ethyl-dec-9-ynoate (III), wherein, the process impurities such as 1-Decanoic acid ethyl ester (VI) and Ethyl non-8-ynoate (VIII) are controlled to less than 0.5%, which becomes the objective of the present invention.

Summary of the invention
In line with the above objective, the present invention provides a process for preparation of highly pure Ethyl-dec-9-ynoate (III), wherein, the process impurities such as 1-Decanoic acid ethyl ester (VI) and Ethyl non-8-ynoate (VIII) are controlled to less than 0.5%.
The present invention provides a process for preparation of Ethyl-dec-9-ynoate (III), which process comprises;
a) oxidizing 9-decyn-1-ol of formula (I) with NaClO2 / NaOCl in presence of TEMPO/ NaH2PO4 in a solvent system to obtain Dec-9-ynoic acid (II);
b) purifying the Dec-9-ynoic acid (II) by converting into its Potassium salt followed by neutralizing with a mineral acid; and
c) esterifying the Dec-9-ynoic acid (II) by treating with Ethanol/Sulphuric acid followed by neutralization to obtain Ethyl-dec-9-ynoate (III).

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a process for preparation of highly pure Ethyl-dec-9-ynoate (III), wherein, the process impurities such as 1-Decanoic acid ethyl ester (VI) and Ethyl non-8-ynoate (VIII) are controlled to less than 0.5%.
The present invention provides a process for preparation of Ethyl-dec-9-ynoate (III), which process comprises;
a) oxidizing 9-Decyn-1-ol of formula (I) with NaClO2 / NaOCl in presence of TEMPO/ NaH2PO4 in a solvent system to obtain Dec-9-ynoic acid (II);
b) purifying the Dec-9-ynoic acid (II) by converting into its potassium salt followed by neutralizing with a mineral acid; and
c) esterifying the Dec-9-ynoic acid (II) by treating with ethanol/sulphuric acid followed by neutralization to obtain Ethyl dec-9-ynoate (III).

The process of the present invention is depicted in scheme I below
Scheme I:

The solvent system is essentially monophasic system selected from the group consisting of Water; Water/Acetonitrile, Water/Acetone.

The reaction of step a) can be conducted at ambient temperature, preferably in the range of 25 to 40°C.

The equivalence of NaOCl and NaClO2 is in the ratio of 0.3-1.7.

The reaction pH of Dec-9-ynoic acid is in the range of 6.5-9.0 and the isolation of Dec-9-ynoic acid is carried out at pH of 3.5-5.0.

The pH of the reaction mixture of Dec-9-ynoic acid is adjusted within the range of 8.5-9.0 to obtain Dec-9-ynoic acid with high purity.

Accordingly, in an embodiment, the invention provides a process for preparation of Dec-9-ynoic acid. In accordance with the process, TEMPO, NaH2PO4 are added to a solution of 9-Decyn-1-ol (I) in a solvent system. The reaction mixture is cooled to -5 to 0° C and added NaClO2 solution followed by NaOCl at the same temperature separately and stirred for 2hrs at ambient temperature. The reaction mixture is then cooled to 20° C and diluted with NaOH solution followed by 5% of Sodium sulphite solution. The pH of the reaction mixture is adjusted to 8.5-9.0 with NaOH solution and washed with Ethyl acetate and the layers are separated. The pH of the aqueous layer is adjusted to 3.0-3.5 with HCl solution and product is extracted in Dichloromethane. The organic layer is washed with water and concentrated to obtain crude Dec-9-ynoic acid (II).

As mentioned previously, the present inventors have observed a new impurity, Non-8-ynoic acid (VII), up to 8% when the oxidation of 9-dec-yn-1-ol (I) is carried out using Jones reagent. Being the same functionality the impurity is carried to the final product and could not be controlled by any purification. Therefore, the present invention has avoided the use of Jones reagent instead it uses TEMPO oxidation, thereby reduces the impurity (VII) to a very low level of 0.01%.

Additionally, the starting material, 9-Decyn-1-ol comprises an impurity, 1-Decanol (IV) in the range of 0.65% to 0.75%. This impurity is also gets oxidized simultaneously along with the compound to 1-Decanoic acid (V), which is further carried to the final product as 1-Decanoic acid ethyl ester (VI). Therefore, to control the impurity (V) to less than 0.5% at the oxidation stage, the present invention has provided a novel technology, wherein the Dec-9-ynoic acid obtained during the oxidation is converted to its Potassium salt and further enriched by treating with Isopropyl alcohol.

Accordingly, in another embodiment, the invention provides a process for purification of the crude Dec-9-ynoic acid (II). The crude Dec-9-ynoic acid thus obtained with purity >98% and impurity (V) up to 0.55% is taken into IPA (435mL), KOH solution was added to the reaction mixture and stirred for 2-3hrs at ambient temperature. Obtained solid was collected by filtration and taken into Water (440mL) and pH of the solution was made acidic using 2N HCl. The product was extracted into Dichloromethane and concentrated, light yellow liquid was obtained with 99.3% purity. The impurity (V) is reduced to 0.21%. By following the process of the present invention, the impurity of 1-Decanoic acid (V) is reduced to less than 0.5% of Dec-9-ynoic acid.

In yet another embodiment, the invention provides a process for preparation of Ethyl dec-9-ynoate (III). Accordingly, pure Dec-9-ynoic acid (II) thus obtained is taken into Ethanol and Sulphuric acid and the reaction mixture is refluxed for 6-8hrs. After completion of the reaction, the solvent is removed and the crude is taken into Dichloromethane and the Ethyl dec-9-ynoate (III) is recovered with 99.16 % purity after the routine workup. Thus the process of the present invention substantially reduced the formation of Ethyl non-8-ynoate (VII).

The structures of the impurities viz., impurity (IV); impurity (V); impurity (VI) impurity (VII) and impurity (VIII) are shown below.
Impurity structure:

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1
Preparation of Dec-9-ynoic acid (II):
TEMPO (2.02g, 0.0129 mol) and NaH2PO4 (35.8g, 0.2584 mol) were added to a solution of 9-dec-yn-1-ol (I) (100g, 0.648 mol) in 1000mL of Acetonitrile. Reaction mixture was cooled to -5 to 0° C. 60mL of NaClO2 solution (prepared by mixing 99.7g of NaClO2 in 300mL of water) followed by 40mL of NaOCl (prepared by mixing 100mL of 9-10% of NaOCl in 100mL of water) were added to the reaction mixture at same temperature separately (It is not advisable to mix NaOCl solution and NaClO2 prior to addition since the mixture appears to be unstable). Remaining solution of NaClO2 followed by NaOCl were added to the reaction mixture separately and stirred for 2hrs at 25 to 30° C. Reaction mixture was then cooled to 20° C and diluted with 2N NaOH solution (300mL) followed by 5% of Sodium sulphite solution (500mL). pH of the reaction mixture was adjusted to 8.5-9.0 by using 2N NaOH solution and washed with Ethyl acetate (200mLX2) and the layers were separated. pH of the aqueous layer was adjusted to 3.0-3.5 using 2N HCl solution (500mL) and product was extracted in Dichloromethane (500mL). Organic layer was washed with water and concentrated.

The crude product, Dec-9-ynoic acid (II) thus obtained with purity >98% and impurity up to 0.55% was taken into IPA (435mL) KOH solution was added to the reaction mixture and stirred for 2-3hrs at ambient temperature. Obtained solid was collected by filtration and taken into Water (440mL) and pH of the solution was made acidic (3.0 to 3.5) using 2N HCl. The product was extracted into Dichloromethane and concentrated. 66gm of light yellow liquid was obtained with 60% yield and 99.3% purity. The impurity was reduced to 0.21%.
Dec-9-ynoic acid (II): 99.3%
1-Decanoic acid (V): 0.21%
Non-8-ynoic acid (VII): 0.01%
Preparation of Ethyl dec-9-ynoate (III):
Dec-9-ynoic acid (66.00g, 0.3923mol) (II) was taken into Ethanol (330mL) and Sulphuric acid (0.99mL). Reaction mixture was refluxed for 6-8hrs. Solvent was concentrated and the crude was taken into DCM (330mL). Organic layer was washed with Water (330mL), 5% NaOH solution (330mL) followed by Water (330mL). Organic layer was passed through a pad of silica gel and concentrated. 67gm of the product was isolated with 99.16% purity and 88% of yield.
Ethyl-dec-9-ynoate (III): 99.16%
1-Decanoic acid ethyl ester (VI): 0.27%
Ethylnon-8-ynoate (VIII): 0.01%
The product, Ethyldec-9-ynoate (III) was confirmed by GCMS, 1HNMR and GC.
1H NMR in CDCl3 d: 0.85-0.89 (t 3H), 1.23-1.48 (m 15H), 1.63-1.69 (m 2H), 2.26-2.31 (t 2H), 4.08-4.15 (q 2H).
Mass: M+199.